Ajay Balwant Chitnis, M.B.B.S.,Ph.D.
Section on Neural Developmental Dynamics
Our goal is to understand how the architecture of the mature nervous system emerges as a consequence of local interactions between cells during early development. We use a combination of cellular, molecular, genetic, and computational tools to understand how cells differentiate in distinct patterns in the various compartments of the zebrafish nervous system. We analyze zebrafish mutants and embryos microinjected with morpholinos or mRNA to alter gene function. We examine mechanisms involved in the division of the prospective neural tissue into compartments with distinct fates and examine how cell differentiation is regulated within each. Our current studies examine how the posterior lateral line system is built in the zebrafish nervous system. Our goal is to define the genetic regulatory network that coordinates cell fate and morphogenesis in the lateral line system and to build computational models, based on these studies, that help us understand how this relatively simple and extremely accessible sensory system in zebrafish builds itself.
The lateral line is a mechanosensory system that detects water flow and consists of sensory organs called neuromasts, which are distributed in a stereotypic pattern over the surface of the zebrafish. Each neuromast has sensory hair cells at its center. The hair cells are surrounded by support cells, which serve as progenitors for the production of more hair cells during growth and regeneration of neuromasts. The development of this superficial sensory system in zebrafish can be observed easily in live embryos with transgenic lines expressing fluorescent proteins in specific subsets of cells of the lateral line system. In addition, a range of genetic and cellular manipulations can be used to investigate gene function.
The function of sensory hair cells in fish neuromasts is remarkably similar to that of hair cells in the vertebrate ear. In addition, the gene-regulatory network that determines specification of neuromast hair cells is very similar to the one specifying hair cell fate in our ear. Like the hair cells in our ears, neuromast hair cells can be damaged by exposure to drugs like aminoglycosides, copper ions, and by exposure to noise. However, unlike our ears, in which loss of hair cells can be permanent, neuromast hair cells have the remarkable ability to regenerate. Hence, the lateral line system serves as an excellent model system for understanding development and developing strategies for engineering regeneration of sensory hair cells.
The posterior lateral line system is initially established by the posterior lateral line primordium (pllp), a cluster of about a 100 cells that migrates from the ear to the tip of the tail periodically depositing neuromasts. Recent studies have shown that the mechanisms that determine and guide collective migration and deposition of cells from the pllp are remarkably similar to those that determine the collective migration of metastatic cancer cells. Hence, the lateral line system has also recently emerged as an excellent system for studying the biology of metastatic cancer cells.
Our expectation is that understanding the genetic regulatory network that coordinates cell fate and morphogenesis of the zebrafish lateral line system will ultimately have a profound impact on translational studies that address a wide range of issues including the development and regeneration of sensory systems and therapies directed at limiting the spread of cancer through metastasis.
Dr. Ajay Chitnis completed his medical training at Grant Medical College, Mumbai in 1983 and then he spent a year at the National Institute of Mental Health and Neuroscience in Bangalore, before beginning his graduate work at the University of Michigan in 1985. Under the guidance of Dr. John Kuwada he showed how axon tracts established in the zebrafish brain by early developing neurons serve as a scaffold to guide growth cones of later developing neurons. Then, as a postdoctoral fellow with Dr. Chris Kintner from 1991-95 at the Salk Institute he showed that Notch signaling, originally identified in Drosophila, has a conserved role in mediating the process of lateral inhibition and determining when progenitor cells are allowed to differentiate as neurons in the Xenopus CNS. The complexity of trying to understand how the pattern of differentiated neurons emerges as a consequence of cell-cell interactions drew him to agent based programming languages like Netlogo, which he has since used to build computational models of various developmental events in the embryo. After a short second postdoctoral position with Dr. Wolfgang Driever, where he did a genetic screen to identify zebrafish with an aberrant pattern of early neurons, he established his Unit in the Laboratory of Molecular Genetics at NICHD in 1997. The screen led to the identification of an E3 ligase Mib1 as new component of Notch signaling pathway. It also led to the analysis of the headless mutant, which provided insight into mechanisms that divide the nervous system into compartments with distinct fate. Now a tenured Senior Investigator and Head of the Section on Neural Developmental Dynamics, Dr. Chitnis and his team are using a combination of cellular, molecular, genetic and computational approaches to understand how the posterior Lateral Line system is established by the posterior Lateral Line primordium as it migrates from the ear to the tip of the tail periodically depositing neuromasts.
Kim CH, Oda T, Itoh M, Jiang D, Artinger KB, Chandrasekharappa SC, Driever W, Chitnis AB. Repressor activity of Headless/Tcf3 is essential for vertebrate head formation. Nature. 2000;407(6806):913-6.
Dalle Nogare D, Somers K, Rao S, Matsuda M, Reichman-Fried M, Raz E, Chitnis AB. Leading and trailing cells cooperate in collective migration of the zebrafish posterior lateral line primordium. Development. 2014;141(16):3188-96.
Nogare DD, Nikaido M, Somers K, Head J, Piotrowski T, Chitnis AB. In toto imaging of the migrating Zebrafish lateral line primordium at single cell resolution. Dev Biol. 2017;422(1):14-23.
Dalle Nogare D, Chitnis AB. A framework for understanding morphogenesis and migration of the zebrafish posterior Lateral Line primordium. Mech Dev. 2017.
Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D, Yeo SY, Lorick K, Wright GJ, Ariza-McNaughton L, Weissman AM, Lewis J, Chandrasekharappa SC, Chitnis AB. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell. 2003;4(1):67-82.
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on November 2nd, 2017